1. Field of the Invention
The present invention relates to a process for the synthesis of acyclovir.
2. Background Information and Related Disclosures
Many synthetic N-substituted derivatives of purines and related nucleosides have been shown to exhibit significant antiviral properties. One notable example is the N-9 alkylated product 9-(2-hydroxyethoxymethyl)guanine, (i.e. acyclovir). It is clearly desirable to have inexpensive and efficient processes for manufacturing such a compound.
The usefulness of any process for manufacturing chemical compounds is gauged by several factors. For example, starting materials should be as simple structurally as feasible (so as to keep their costs low). The process is more efficient if intermediates do not require isolation and/or purification, since these procedures result in additional steps and lower yield. The process should yield a product that is free of byproducts (e.g., undesired isomers and/or chemical reagents). Shortcomings in any of the above parameters result in increased manufacturing costs, which impacts negatively on the desirability of the process.
The simplest synthetic approach to the N-9 substituted guanine compounds involves direct alkylation of a protected guanine base. However, there are significant drawbacks to this approach. In many reported processes, guanine protected by acyl groups (for example, diacetylguanine) is employed as the protected guanine base. However, acyl groups prove difficult to remove at the completion of the process, resulting in lower yields. Also, known alkylation processes are not regiospecific for the N-9 position of the protected guanine base, and result in a mixture of N-9 and N-7 alkylation products. The undesired N-7 isomer is difficult to separate from the desired N-9 isomer, requiring chromatography for isolation. Chromatographic separation on a commercial scale is most undesirable, because of the increased costs associated with such a separation (cost of solvents and stationary phase, low yields of desired product, etc).
Surprisingly, an efficient and selective process has been discovered for preparing the substituted guanine compound acyclovir. The process avoids the use of acyl groups for protection of guanine, is essentially specific for the preparation of the N-9 isomer (thus eliminating the need for the chromatographic separation of the N-9/N-7 isomer mixture), provides good yields, requires simple starting materials and reaction conditions, and is carried out from start to finish in a single reaction vessel.
One important aspect of the invention relates to the choice of the acid catalyst, which is critical to the success of the process. Use of common acid catalysts such as sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, gives low yields and undesired byproducts. Only certain selective alkylation catalysts give high yields and highly selective N-9 alkylation.
Previous processes for the preparation of acyclovir and similar compounds are disclosed in U.S. Pat. Nos. 4,355,032, 4,360,522, 4,621,140, and 5,250,535, European Patent Applications 152,965, 532,878, and 72,027, and JP 5213903. Syntheses of related compounds are disclosed in Nucleosides Nucleotides, 8(2), pp 255-256 (1989), Zhongguo Yaoke Daxue Xuebao, 23(1), pp 43-44 (1992), Org. Prep. Proced. Int, 25(4), pp 375-401 (1993), J. Med. Chem., 26(5), 759-61 (1983), Synth. Commun., 18(14), 1651-60 (1988), and Chem. Pharm. Bull., 36(3), 1153-1157 (1988).